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Whole-animal, high-resolution imaging of AAV tropism for the nervous system

Award Number: R21NS130139
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/26/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Whole-animal, high-resolution imaging of AAV tropism for the nervous system - PROJECT SUMMARY/ABSTRACT Adeno-Associated Viruses (AAVs) are the most commonly used gene therapy vector and AAV technology is posed to deliver new treatments for a wide range of previously incurable conditions. AAVs are non-pathogenic to humans and infect non-dividing cells, making them ideal vectors for targeted regulation of gene expression in the human central and peripheral nervous system (CNS/PNS). These highly attractive factors have broadly increased interest in therapeutic AAVs; however, existing AAV vectors require very high doses to express transgenes in CNS/PNS targets at levels that mitigate pathology. The resulting dose-dependent toxicities in other organs have led to clinical failures and unpredictable off-target delivery, which is a major limitation of modern gene therapy. There is a critical need for high-throughput, comprehensive profiling of viral tropism and transduction efficiency that could speed development of safe and effective AAVs. AAV tropism is typically determined using immunohistochemical techniques, which are the gold standard for detection of transgene expression. However, these methods are labor-intensive and permit testing of only a small number of pre-determined tissues. Efficient and comprehensive AAV tropism profiling technologies would facilitate discovery of AAV variants with greater CNS/PNS tropism by enabling fast iterative testing and direct comparison of AAV mutant vectors. My long-term goal is to develop novel gene therapy treatments for peripheral nerve injuries. The objective of this proposal is to test feasibility of using a custom hyperspectral whole-body imaging cryomacrotome (BioSlice) for rapid, automated evaluation of AAV tropism for the nervous system. Our proposed experiments combine two powerful technologies—transgenic fluorescent reporter mice and whole-body, high-resolution hyperspectral wide-field imaging—to detect AAV transduction and provide a new approach to AAV tropism profiling. In Aim 1, we will use the BioSlice to search for off-target delivery in Ai14 mice that have been injected with three AAV variants that have known tropism for the CNS/PNS. In Aim 2, we will test whether the BioSlice can detect multiplexed AAVs using distinct fluorescent reporters in the same animal, and examine effects on AAV tropism related to injection site. Completion of these aims will deliver an innovative application of an advanced imaging technology to address a fundamental bottleneck in AAV development. If successful, our work will provide robust proof-of-concept that the BioSlice can be used to rigorously evaluate pre-clinical AAVs for therapeutic use. This transdisciplinary approach has the potential to enable tropism discovery through unbiased investigation of all tissues in the mouse, thereby accurately modeling potential off-target delivery and negative side-effects across AAV serotypes, expression cassettes and injection sites.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	DARTMOUTH-HITCHCOCK CLINIC	1 MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/17/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $443,862 )
2022	2022	DARTMOUTH-HITCHCOCK CLINIC	ONE MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/25/2022	NEW	$443,862
2022	2022	DARTMOUTH-HITCHCOCK CLINIC	ONE MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/26/2022	NEW	$0
														Subtotal = $443,862

Grand Total All Awards = $443,862

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Whole-animal, high-resolution imaging of AAV tropism for the nervous system

Award Number: R21NS130139

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/26/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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